nef reaction and its applications in chemistry
TRANSCRIPT
NEF REACTION AND ITS
APPLICATIONS
PRESENTED BYShantanu gupta
4th sem. M. Tech(PHARM)Pharmaceutical Technology (Process Chemistry )
2FLOW OF PRESENTATION
•INTRODUCTION
•MECHANISM
•MODIFIED NEF REACTIONS
•APPLICATIONS
•CONCLUSION
3INTRODUCTION
Interconversion of functional groups represents an important aspect in every process leading to the synthesis of structurally defined compounds
Nef reaction involves acid hydrolysis of a salt of primary or secondary nitroalkane to yield carbonyl compounds
It was first reported by Nef in 1894
R R1
NO2
R R1
OBASE
ACID+ N2O
4
R
NO2
R1
RR1 R
R1
RR1
RR1
NH2
O
-HNO2
[H]N[H]C
NEF
GENERAL TRANSFORMATIONS OF NITRO GROUP
Tetrahedron, 2004 ,60 ,1017–1047.
5HISTORY
Nef reaction is named after the John Ulric Nef
He was graduated from harvard university
The discovery of nef reaction and papers concerned with the divalent carbon are his major acheivements
June 14, 1862 – August 13, 1915
6 MECHANISM
R R1
NO O
R R1
NO O
R R1
NO OH
R R1
NHO OH
R R1
NHO OH
R R1
O
HOH
H OH2
H OH2
OHH
H2O H2O
R R1
NO
OH
-H, -H2O
H OH2
HN
O
Nitronic acidNitronate salt
Iminium ion
Nitroso alkanol
RR
OH
+
Oxonium ionHyponitrous acid
-H
7Side reactions
O
NO2 NaO
OO
O
H3O
Heat
salt of Nitroketone
H3C NO2OH O2N C
HCH
NO
Methazonate ion
Self condensation
Dimerization
RR1CHNO2 RR1C(NO)NO2 RC(NO)2=NOH
NaOH
H+
R1=H
pseudonitroles nitrolic acid
Formation of pseudonitroles
J. Am. Chem. Soc. 1955, 77 ,2622
8S S S
OH
NO2
OH
OH
NO2
OH
NO2+
65% 35%
Base
HCl
Dehydration
Nitrocompounds which fail to react under nef conditions
OH
OHOH
NO2
OH
OH
Nitrodeoxyinositol
N
HO RNO2
CH2NO2CH3
CNNC
OCH3OCH3
OCH3
CH(NO2)R
CH2CH=CH2
J. Am. Chem. Soc. 1948, 70, 746
9
MODIFIED NEF REACTIONS
10
CO2Me
NO2
CO2Me
H
O
t-BuOH,THF
,rt, 73%O O
R
R1
NO2R
R1
COOHKMNO4
KOH,K2HPO4t-BuOH,rt
R=EtO2CCH2, R1=CO2Et 96%
R=OH(CH)2 R=H 99%
R
R1OR
O
H
OXIDATIVE METHODS
DMD
Synlett 1998, 1335
11 NO2
O O
O
O ONaOH-Na2HPO4
OXONE rt,87%
Oxone
Synth. Commun. 1998, 28, 3054
R
R'NO2
R
R'N
O
ON
O
RR'
O
O
NRR' O
OO
R
OSO3H
NO2-
O2SO3HOH-
O
MECHANISM
12
O
NO2
O
O
TiCl3-H2O-glyme
base
Mc murry method
REDUCTIVE METHODS
J. Org. Chem. 1973, 38, 4367
13
NO O
NO OTiCl2N
O O
N O
NOH
O
TiCl3
TiCl3
titanium nitronatenitroso derivative
iminium ion
B-
NO OTiCl2
oxime
J. Org. Chem. 1973, 38, 4367.
MECHANISM
14
Other methods
O ONO2
COOMe
O OO
COOMe
DBU
MeCN,60 oC80%
Tetrahedron Lett. 2002, 43, 5233
R R
NO2
N
N
R
RN
O
O
HO N
R R
ON
RR
HO
OR R
O
DBU
-HNO
MECHANISM
H
oxaziridine
hydroxynitroso derivative
15
APPLICATIONS
16
CHOR
CH2NO2
CHOHR
*
CHOOHH
R
CHOHHO
R
CH=NO2NaCHOHR
+
2N NaOHCH3NO2
CH3ONain CH3OH
H2SO4
*
1-nitro-1-deoxy sugar alcohol
In carbohydrate chemistry
Used as chain extension method of aldoses
J. Biol. Chem. 1949, 180,55-58
17
BnO NH
O
R
SO2Ph
BnO NH
O
R
NO2NaH-MeNO2
THF,rt77-90%
BnO NH
O
R
COOH
1. KMnO4Phosphate buffer
2. 2N HCl70-90%
amidoalkyl phenylsulphone
N-carbobenzoxy aminoacid
R= PhCH2CH2 90%
Synthesis of α-amino acids
Tetrahedron Lett. 1999, 40, 4449
18
NO2
O
NO2
O
O
OO
O
0.5 N NaOH
MeOH,93%
1. Al2O32. 30%H2O2,K2CO33. 0.5N NaOH
1. MeONa,MeOH2. H2SO4,90%
Al2O3,78%
allylrethrone
Synthesis of allylrethrone
It is an important component of insecticidal pyrethroid
Synthesis. 1993, 687
18
19Synthesis of β-lactum building blocks
N
NO2
O
R
ArN
N
O
R
Ar
OBu3SnO
Bu3SnH
CH2Cl2, 80-95%
1. O3,CH2Cl2,-78 0C2. Me2S,50-78%
R=Ph Ar=PhR=2,5Me2C6H3 Ar=Ph
stannyl nitronates
N
O
O
R
Ar
J. Org. Chem. 1990, 55, 2070
20
Conclusion
Nef reaction dates back a century ago but still it has significance due to its applicability in conversion of nitrocompounds to carbonyl compounds
Modified nef reactions uses oxidising and reducing agents which helps in the synthesis of various biologically active compounds
It also has applications in carbohydrate chemistry as a chain-extension method of aldoses
21
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